Back to resultsPharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function
Primary Purpose
Nonalcoholic Steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC)
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Cilofexor
Sponsored by
About this trial
This is an interventional treatment trial for Nonalcoholic Steatohepatitis (NASH)
Eligibility Criteria
Key Inclusion Criteria:
Cohort 1:
- Individuals with mildly impaired and normal hepatic function.
- Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Cohort 2:
- Individuals with moderately impaired and normal hepatic function.
- Individuals with moderate hepatic impairment must have a score of 7-9 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Cohort 3:
- Individuals with severely impaired and normal hepatic function.
- Individuals with severe hepatic impairment must have a score of 10-15 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Cohort 1: Mild Hepatic Impairment
Cohort 1: Normal Hepatic Function
Cohort 2: Moderate Hepatic Impairment
Cohort 2: Normal Hepatic Function
Cohort 3: Severe Hepatic Impairment
Cohort 3: Normal Hepatic Function
Arm Description
Participants with mild hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Matched normal hepatic function participants to mild hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Participants with moderate hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Participants with severe hepatic impairment will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).
Matched normal hepatic function participants to severe hepatic impairment participants will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).
Outcomes
Primary Outcome Measures
Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
PK Parameter: AUCinf of Cilofexor
AUCinf is defined as the concentration of drug extrapolated to infinite time.
PK Parameter: Cmax of Cilofexor
Cmax is defined as the maximum concentration of drug.
PK Parameter: %AUCexp of Cilofexor
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
PK Parameter: Clast of Cilofexor
Clast is defined as the last observable concentration of drug.
PK Parameter: Tmax of Cilofexor
Tmax is defined as the time (observed time point) of Cmax.
PK Parameter: Tlast of Cilofexor
Tlast is defined as the time (observed time point) of Clast.
PK Parameter: λz of Cilofexor
λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.
PK Parameter: CL/F of Cilofexor
CL/F is defined as the apparent oral clearance following administration of the drug.
PK Parameter: Vz/F of Cilofexor
Vz/F is defined as the apparent volume of distribution of the drug.
PK Parameter: t1/2 of Cilofexor
t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
Secondary Outcome Measures
Percentage of Participants Experiencing Treatment-Emergent Adverse Events
Percentage of Participants Who Experienced Graded Laboratory Abnormalities
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose up to and including the date of last study drug dose plus 30 days. The most severe graded abnormality from all tests was counted for each participant.
Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4)
AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4)
Cmin for C4 is defined as the minimum observed concentration of C4. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19)
AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19)
Cmax for FGF19 is defined as the maximum observed concentration of FGF19. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02808312
Brief Title
Pharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function
Official Title
A Phase 1 Open-Label, Parallel-Group, Adaptive, Single-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of GS-9674 in Subjects With Normal and Impaired Hepatic Function
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
July 13, 2016 (Actual)
Primary Completion Date
October 16, 2018 (Actual)
Study Completion Date
October 16, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective of this study is to evaluate the single-dose pharmacokinetics of cilofexor in adults with impaired hepatic function relative to matched, healthy controls with normal hepatic function.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1: Mild Hepatic Impairment
Arm Type
Experimental
Arm Description
Participants with mild hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Arm Title
Cohort 1: Normal Hepatic Function
Arm Type
Experimental
Arm Description
Matched normal hepatic function participants to mild hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Arm Title
Cohort 2: Moderate Hepatic Impairment
Arm Type
Experimental
Arm Description
Participants with moderate hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Arm Title
Cohort 2: Normal Hepatic Function
Arm Type
Experimental
Arm Description
Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets).
Arm Title
Cohort 3: Severe Hepatic Impairment
Arm Type
Experimental
Arm Description
Participants with severe hepatic impairment will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).
Arm Title
Cohort 3: Normal Hepatic Function
Arm Type
Experimental
Arm Description
Matched normal hepatic function participants to severe hepatic impairment participants will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).
Intervention Type
Drug
Intervention Name(s)
Cilofexor
Other Intervention Name(s)
GS-9674
Intervention Description
Tablet(s) administered orally in a fed state on Day 1
Primary Outcome Measure Information:
Title
Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
Description
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: AUCinf of Cilofexor
Description
AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: Cmax of Cilofexor
Description
Cmax is defined as the maximum concentration of drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: %AUCexp of Cilofexor
Description
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: Clast of Cilofexor
Description
Clast is defined as the last observable concentration of drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: Tmax of Cilofexor
Description
Tmax is defined as the time (observed time point) of Cmax.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: Tlast of Cilofexor
Description
Tlast is defined as the time (observed time point) of Clast.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: λz of Cilofexor
Description
λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: CL/F of Cilofexor
Description
CL/F is defined as the apparent oral clearance following administration of the drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: Vz/F of Cilofexor
Description
Vz/F is defined as the apparent volume of distribution of the drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Title
PK Parameter: t1/2 of Cilofexor
Description
t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
Time Frame
≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose on Day 1
Secondary Outcome Measure Information:
Title
Percentage of Participants Experiencing Treatment-Emergent Adverse Events
Time Frame
Day 1 up to Day 31
Title
Percentage of Participants Who Experienced Graded Laboratory Abnormalities
Description
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose up to and including the date of last study drug dose plus 30 days. The most severe graded abnormality from all tests was counted for each participant.
Time Frame
Day 1 up to Day 31
Title
Pharmacodynamic (PD) Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for α-hydroxy-4-cholesten-3-one (C4)
Description
AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
Time Frame
0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
Title
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmin for α-hydroxy-4-cholesten-3-one (C4)
Description
Cmin for C4 is defined as the minimum observed concentration of C4. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
Time Frame
0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
Title
PD Parameter: Mean Day 1/ Day -1 Ratio of AUC2-12 for Fibroblast Growth Factor 19 (FGF19)
Description
AUC2-12 is defined as area under the curve calculated by the trapezoidal rule for the time from 2 to 12 hours. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
Time Frame
0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
Title
PD Parameter: Mean Day 1/ Day -1 Ratio of Cmax for Fibroblast Growth Factor 19 (FGF19)
Description
Cmax for FGF19 is defined as the maximum observed concentration of FGF19. For PD assessments on Day -1, participants were administered a single oral dose of placebo-to-match cilofexor tablet on Day -1; the reported Time Frame is with respect to the placebo dosing.
Time Frame
0.5 hour predose, ≤ 5 minutes predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours postdose on Day -1 and Day 1; 4.5 hours postdose on Day -1; 24, 48, 72, and 96 hours postdose on Day 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Key Inclusion Criteria:
Cohort 1:
Individuals with mildly impaired and normal hepatic function.
Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Cohort 2:
Individuals with moderately impaired and normal hepatic function.
Individuals with moderate hepatic impairment must have a score of 7-9 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Cohort 3:
Individuals with severely impaired and normal hepatic function.
Individuals with severe hepatic impairment must have a score of 10-15 on the CPT classification at screening without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 2 months prior or within the screening period.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
City
Miami
State/Province
Florida
ZIP/Postal Code
33014
Country
United States
City
Orlando
State/Province
Florida
ZIP/Postal Code
32809
Country
United States
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37920
Country
United States
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
City
Auckland
ZIP/Postal Code
1640
Country
New Zealand
12. IPD Sharing Statement
Learn more about this trial
Pharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function
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